Sugar-modified nucleoside analogues such as 3'-azido-3'-deoxythymidine and 2'3'-dideoxynucleosides have been used as transcription inhibitors for a variety of viral infections. Recently, certain nucleoside analogues built on a bicyclic sugar, 3'-endo 4',6'-methanocarbocyclic nucleosides, demonstrated potent activity against HSV, HMCV, and EBV. The AZT TP analogue of the 4',6'-methanocarbocyclic thymidine is an equipotent inhibitor of HIV reverse transcriptase as is AZT (Marquez et al. J. Med. Chem. 1996, 39, 3739-3747; 1998, 20, 2780-2789).
A number of other bicyclic-sugar nucleosides have also been reported. Unfortunately, these nucleosides showed either no or weak biological activity. Apparently, each type of bicyclic-sugar moiety has a unique geometrical shape, and a unique interaction pattern with biological targets. Bicyclic-sugar nucleosides could be useful as antiviral compounds, but to date have not been intensively explored.
In addition to the utility as pharmaceutical ingredients, nucleoside analogues built on bicyclic-sugar moieties can be useful as building blocks for oligonucleotides. Oligonucleotides are known to sequence-specifically bind to DNA and RNA, therefore, they can be potentially useful as antisense inhibitors of gene expression or as gene probes.
A molecule can be "locked" into desired conformation by chemically adding a molecular bridge onto the molecule. The conformationally-modified nucleosides can then be used to form conformationally-modified oligonucleotides that have certain desired, geometrical shapes and entropy advantages over unmodified nucleosides. Among known bicyclic-sugar modified oligonucleotides, those containing 2',4'-bridged nucleosides demonstrate excellent hybridization to complementary DNA and RNA (Koshkin et al. Tetrahedron 1998, 54, 3607-3630; Wang et al. Bioorg. Med. Chem. Lett. 1999, 9, 1147-1150).
In addition to sugar-modified oligonucleotides, tremendous efforts have been made to explore backbone-modified oligonucleotides. It appears that both favorable sugar and backbone modifications can enhance oligonucleotides' potential as antisense therapeutics or as gene-specific diagnostics.
The present invention describes a combination of favorable backbones and conformationally locked, 3'-endo sugar moieties in nucleosides and oligonucleotides. The effects from the conformationally locked sugar and the modified, favorable backbones can be synergetic, therefore, the oligonucleotides containing these modifications can have superior hybridization to DNA or RNA, as well as excellent biological stability.